The aims of this proposal are to (1) improve comparative modeling so that atomic level accuracy models can be routinely generated starting from structures of homologous proteins, (2) transform the process of NMR structure determination by making possible the determination of atomic level accuracy models without side chain assignments, and (3) enable the determination of high resolution structures from 3-4.5 E resolution density maps. These methodological advances will be extended to enable structure determination of membrane proteins and large homo-oligomers based on datasets not sufficient to allow structure determination using conventional methods.
The proposed work could transform the process of macromolecular structure determination, making it possible to determine accurate structures rapidly with less cost and effort, and to determine atomic level structures for proteins and complexes for which this is not currently possible. Such structures could provide insight into fundamental biological processes and the basis for disease causing mutations, and allow the structure based design of new therapeutics.
|Kim, David E; Dimaio, Frank; Yu-Ruei Wang, Ray et al. (2014) One contact for every twelve residues allows robust and accurate topology-level protein structure modeling. Proteins 82 Suppl 2:208-18|
|Demers, Jean-Philippe; Sgourakis, Nikolaos G; Gupta, Rashmi et al. (2013) The common structural architecture of Shigella flexneri and Salmonella typhimurium type three secretion needles. PLoS Pathog 9:e1003245|
|DiMaio, Frank; Zhang, Junjie; Chiu, Wah et al. (2013) Cryo-EM model validation using independent map reconstructions. Protein Sci 22:865-8|
|Song, Yifan; DiMaio, Frank; Wang, Ray Yu-Ruei et al. (2013) High-resolution comparative modeling with RosettaCM. Structure 21:1735-42|
|DiMaio, Frank; Echols, Nathaniel; Headd, Jeffrey J et al. (2013) Improved low-resolution crystallographic refinement with Phenix and Rosetta. Nat Methods 10:1102-4|
|Adams, Paul D; Baker, David; Brunger, Axel T et al. (2013) Advances, interactions, and future developments in the CNS, Phenix, and Rosetta structural biology software systems. Annu Rev Biophys 42:265-87|
|Lange, Oliver F; Baker, David (2012) Resolution-adapted recombination of structural features significantly improves sampling in restraint-guided structure calculation. Proteins 80:884-95|
|Schmitz, Christophe; Vernon, Robert; Otting, Gottfried et al. (2012) Protein structure determination from pseudocontact shifts using ROSETTA. J Mol Biol 416:668-77|
|DiMaio, Frank; Leaver-Fay, Andrew; Bradley, Phil et al. (2011) Modeling symmetric macromolecular structures in Rosetta3. PLoS One 6:e20450|
|Song, Yifan; Tyka, Michael; Leaver-Fay, Andrew et al. (2011) Structure-guided forcefield optimization. Proteins 79:1898-909|
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